Project Summary/Abstract In age-related neurodegenerative disorders like Alzheimer's disease, the loss of cortical neurons is the likely cause of progressive cognitive impairments. In contrast, in normal aging, the cause of the relatively mild cognitive impairments that develops remains unclear as cortical neurons are not lost. However, cortical neurons have been shown to become dysfunctional in a number of ways ranging from deterioration of myelinated axons that interconnect cortical areas to changes in action potential generation at the soma. A critical functional component of cortical information processing is the microcolumn, a vertical array of neurons that are tightly interconnected and that work together to process fundamental information. The classic example is the orientation column of visual cortex. Accumulating evidence suggests that age-related changes in microcolumnar organization may be an important marker of age-related cortical dysfunction. Age-related alterations in microcolumns will be addressed using archival brain material available from a study of rhesus monkeys in which all animals are behaviorally tested to characterize cognitive status and the brains are harvested for neurobiological study. The first aim is to acquire whole brain photomontages to quantitatively assess microcolumnar structure throughout the entire cerebral cortex of both male and female rhesus monkeys that cover the entire adult life span. This will identify regions where the greatest age-related disruptions in microcolumns occur and where those changes are most strongly related to cognitive impairments. This will test the hypothesis that regional alterations in microcolumnar structure and associated cortical dysfunction account for age-related cognitive impairments. Based on the identification of most affected cortical areas, Aim 2 will utilize immunohistochemical methods to label intracellular cytoskeletal elements of dendrites of cortical neurons. These will be analyzed to test the hypothesis that alterations in dendritic structure are associated with the disruption of microcolumnar architecture. Similarly, Aim 3 will utilize NeuN immunohistochemistry to uniquely separate neurons from glia allowing for separate analysis of glia changes. This aim will test the hypothesis that disruptions in glial distribution are associated with age-related disruption of microcolumns. For both dendrites and glia, cross correlation methods will be used to quantify the relationship to microcolumn changes and for all three aims multivariate methods will assess the relationship with cognitive impairments. These data will generate testable mechanistic hypotheses regarding the causes of microcolumnar dysfunction and will provide insight into the basis of age-related cortical dysfunction and cognitive impairment. Future directions for this study will include analysis of the small but functionally significant population of GABAergic neurons and the distribution of intercellular adhesion molecules that bind the cortex together. Project Narrative In normal aging, cognitive dysfunction occurs without the loss of cortical neurons yet evidence indicates disruption of the architecture of vertical arrays of cortical neurons that are organized as microcolumns. These microcolumns are a fundamental computational unit of the cerebral cortex, and their age-related degradation correlates with age-related cognitive impairment. These will be studied using advanced quantitative methods and compared with changes in dendritic structure and glia cells to determine the processes underlying age- related cognitive impairments.